New Ideas Grants
2018-2019 New Ideas Project Awardees
Elucidation of splicing-based mechanisms underlying cell fate control that represent targets in regenerative medicine applications
Benjamin Blencowe, University of Toronto ($75,000)
Alternative splicing (AS) is a regulatory process that allows a single gene to generate multiple different RNA transcripts and proteins. We have previously shown that specific AS events are critical for the control of embryonic stem cell (ESC) pluripotency, differentiation, and efficient reprogramming. However, the function of most AS events associated with these processes is not known. Our project aims to employ new methods to systematically define the roles of AS events in reprogramming and differentiation. This will be accomplished by applying a novel CRISPR-based screen we have developed to systematically delete genetic elements (i.e. alternative exons) to determine their role in controlling ESC pluripotency and neuronal cell differentiation. This method will be applied to ESCs, which will then be monitored for changes in pluripotency and neuronal differentiation-potential using high-throughput phenotyping assays. Furthermore, we will utilize another new CRISPR-based screen we have developed that employs dual-fluorescence splicing reporters to define combinations of regulators that can be manipulated to enhance reprogramming and neuronal differentiation. This research will establish generalizable, genome-wide approaches for the identification of exons and corresponding regulators of AS programs, and as such is expected to have broad utility in future research and therapeutic applications.
A matter of timing: how the circadian clock regulates intestinal regeneration.
Phillip Karpowicz, University of Windsor ($75,000)*
The human body has daily 24-hour cycles, known as circadian rhythms. Circadian rhythms are hardwired through a system of genes and hormones present in all the cells and tissues of the body. Shift-work, frequent travel, and artificial lighting can disturb circadian rhythms, and increase a number of serious illnesses. Our lab recently identified circadian rhythms in regeneration of the mouse small intestine. To better understanding this process, we will investigate circadian rhythms in both mouse and human organoids, artificial mini-organs grown in the lab from stem cells that can be used to model human diseases. Our study will investigate
a population of stem cells responsible for regeneration of intestinal tissue during injury and disease. Understanding circadian rhythm in organoid cultures will provide a timing for regeneration, and inform clinicians about the best time for therapeutic interventions. This knowledge could be applied to patients with inflammatory bowel disease or colorectal cancer, as well as patients treated by radiation or surgery.
Developing new reprogramming strategies for cell replacement therapy of glaucoma
Pierre Mattar, Ottawa Hospital Research Institute ($75,000)*
Glaucoma is a leading cause of blindness, with an estimated 400,000 Canadians affected. Glaucoma typically arises from an increase in intraocular pressure. Although often treatable, the buildup of intraocular pressure causes the death of retinal ganglion cells (RGCs), which are responsible for transmitting information from the eye to the brain. A large proportion of affected individuals are diagnosed too late to prevent RGC death, or progress to blindness despite treatment. Cell replacement therapy is a strategy that could potentially allow patients to recover their lost vision. Recent advances have demonstrated the promise of RGC transplantation for treating glaucoma. However, efficient generation of RGCs from patient-derived cells needs to be further developed in order to bring cell replacement therapy to the clinic. This project will use genetic tools to reprogram pluripotent stem cells towards RGCs as well as reprogram fibroblast cells directly into RGCs. This will lay the groundwork for future studies evaluating whether transplantation of RGCs produced in the laboratory can integrate into glaucomatous retinas and lead to functional repair.
Making new neurons from resident brain cells: a new therapy for stroke repair?
Maryam Faiz, University of Toronto ($74,946)*
Co-Investigator: Cindi Morshead, University of Toronto
Stroke is the leading cause of adult disability in Canada and the third leading cause of death. Current interventions are limited to restoring blood flow and preventing cell death during the acute phase following stroke. The need for novel therapies to promote plasticity and beneficial functional outcomes, including the regeneration of lost tissue, is clear. Reprogramming (the conversion of one cell type to another) offers one such possibility for neural repair after stroke, whereby reprogrammed cells would replace those lost to injury. Attempts at in vivo reprogramming in the brain have demonstrated successful conversion of astrocytes to neurons at the site of injury. However, the outcome of reprogramming in terms of functional recovery, the most clinically relevant measure of success, has not been examined. To address this gap, our research will investigate whether reprogramming of astrocytes to neurons improves the long-term disability caused by stroke.
Collaborative laboratory-based study of stem cell therapies: Preclinical Multicenter Acute lung injury Trials In Canada (PreMATIC)
Manoj Lalu, Ottawa Hospital Research Institute ($74,997)*
Dean Fergusson, Ottawa Hospital Research Institute
Bernard Thebaud, Ottawa Hospital Research Institute
Haibo Zhang, St. Michael’s Hospital
Ninety percent of ‘bench-to-bedside’ (i.e. preclinical-to-clinical) efforts fail to produce usable therapies. A lack of robust data from laboratories may be contributing these failures, since bench findings are often irreproducible and lack methodological rigor; a direct solution to this may be multicenter preclinical trials. Similar to clinical multicenter studies, a multicenter preclinical trial would overcome issues such as a lack of power and small sample sizes, and will account for heterogeneity of laboratories and personnel. Our team is interested in lung injury in patients with acute respiratory distress syndrome. Mesenchymal stromal cell derived exosomes (MEX) may be a novel therapy to help treat this condition. This project will use a multicenter preclinical trial approach to test the effect of MEX in a model of acute lung injury. Four laboratories in two centers will use harmonized protocols to induce lung injury and perform treatment with MEX. In order to generate precise estimates of efficacy, the study will employ methods to reduce risk of bias and will have a central analysis of outcomes. If exosomes prove beneficial, our study may lead to ‘cell-free cell-therapy’ in which MSC exosomes are administered in lieu of the whole cell. Our novel approach, will be the first multicenter preclinical study in Canada and the first multicenter evaluation of any stem cell product globally. Knowledge gained through this approach will allow a better understanding as to why preclinical-to-clinical translation has been riddled with failures.
Boosting cellular energy signals in muscle stem cells as a therapy for muscular dystrophy.
Keir Menzies, University of Ottawa ($75,000)*
Muscular dystrophy is a life-threatening muscular disorder, to which there is no cure. Part of the difficulty in treating this disorder is the fact that this is a genetic disease that affects a key protein, dystrophin, that maintains the structure of the muscle. Our project aims to examine the potential to alter the functional capacity of muscle stem cells (the cells responsible for muscle regeneration) to improve outcomes of patients with muscular dystrophy. Our research has previously found that hyper-activated proteins (PARPs) are responsible for a reduction in energy generation by the powerhouse of the cell, also known as the mitochondria. Extending our findings, we suspect that alterations in PARP activity leads to reduced energy function thereby disrupting muscle regeneration in muscular dystrophy. In this project, we will compare PARP activity in mouse models of muscular dystrophy to normal mice, to better understand the relationship on muscle stem cell function and regeneration. Through understanding of this family of proteins, we hope to design new therapies for muscular dystrophy.
2017-2018 Awardees (*co-funded by Medicine by Design; **Funded by Medicine by Design):
- The impact of environmental pollutants on pancreas development ($75,000) Project Leader: Jennifer Bruin (Carleton University)
- A 3D model of muscle to study potential therapies for Duchenne muscular dystrophy* ($75,000) Project Leader: Penney M. Gilbert (University of Toronto)
- Tailoring donor lungs to control immune response before transplant** ($75,000) Project Leader: Stephen C. Juvet (University Hospital Network)
- Improving the creation of bile duct cells to model liver disease** ($75,000) Project Leader: Binita M. Kamath (SickKids Research Institute)
- A computational modelling platform to support imaging and tissue design** ($75,000) Project Leader: John Parkinson (SickKids Research Institute)
- Understanding radial glial cell response to neural injury at a single cell level** ($75,000) Project Leader: Bret Pearson (SickKids Research Institute)
- A therapeutic strategy for treating Duchenne Muscular Dystrophy ($75,000) Project Leader: Michael A. Rudnicki (Ottawa Hospital Research Institute)
- Magnetic resonance imaging to assess stem cell treatments for lung diseasel** ($75,000) Project Leader: Giles Santyr (SickKids Research Institute)
- Autism spectrum disorder drug testing using human neurons ($75,000) Project Leader: Karun Singh (McMaster University)
- Clinical investigation of cell therapy to treat age-related osteoporosis ($75,000) Project Leader: William L Stanford (Ottawa Hospital Research Institute)
- Making new blood vessels for life-threatening lung diseases in newborns ($75,000) Project Leader: Bernard Thébaud (Ottawa Hospital Research Institute)
- New ways to stimulate the production of insulin-producing cells to treat diabetes* ($75,000) Project Leader: Michael B. Wheeler (University of Toronto)
Past Awardees (*co-funded by Medicine by Design):
- Control of immune tolerance toward allograft cell transplants ($50,000) Project Leader: Andras Nagy (The Lunenfeld-Tanenbaum Research Institute) 2015-16
- Dissolving scar tissue in spinal cord injuries improve candidacy and effects of stem cell transplants* ($49,988) Project Leader: Charles Tator (University Health Network) 2015-16
- Sole fuel source to enhance pluripotency ($50,000) Project Leader: Dean Betts (Western University) 2015-16
- An injectable biomaterial system for the delivery of stem cells in the treatment of retinal disease ($50,000) Project Leader: Heather Sheardown (McMaster University) 2015-16
- Activating enhancers to improve reprogramming efficiency* ($50,000) Project Leader: Jennifer Mitchell (University of Toronto) 2015-16
- Better maturation of iPS-derived heart cells ($49,200) Project Leader: John Coles (SickKids Research Institute) 2015-16
- Protein inactivation by agrochemicals as a mechanism underlying development of Autism Spectrum Disorder ($49,994) Project Leader: John Vessey (University of Guelph) 2015-16
- Injectable, tissue engineered scaffold for delivery of cardiac patches* ($50,000) Project Leader: Milica Radisic (University of Toronto) 2015-16
- Heart tissue repair via immune cell growth factors* ($50,000) Project Leader: Slava Epelman (University Health Network) 2015-16
- Intestinal stem cells and gut microbiota in early postnatal development and necrotizing enterocolitis ($49,980) Project Leader: Tae-Hee Kim* (SickKids Research Institute) 2015-16
- Biomimetic surfaces for directed differentiation of lung stem cells * ($49,983) Project Leader: Tom Waddell (Univerisity Health Network) 2015-16
- Mechanisms regulating differentiation in hemangioma stem cells ($49,500) Project Leader: Zia Khan (Western University) 2015-16
- TIMP-engineered niches for liver progenitor cell expansion ($75,000) Project Leader: Rama Khokha (University Health Network) 2014-15
- Control of RNA translation into proteins in human stem cells, neurons and disease ($75,000) Project Leader: James Ellis (SickKids Research Institute) 2014-15
- Engineering a functional human thymus from pluripotent stem cells ($75,000) Project Leader: Peter Zandstra (University of Toronto) 2014-15
- Role of short RNA fragments in mediating the anti-inflammatory effects of bone marrow stem cells in sepsis ($75,000) Project Leader: Duncan Stewart (Ottawa Hospital Research Institute) 2014-15
- Genomic correction of cardiac sarcomeric protein mutations in iPSC-derived cardiomyocytes ($75,000)Project Leader: John Coles (SickKids Research Institute) 2014-15